We have demonstrated that ultrasonic drug release using mild hyperthermia is feasible. Here, our goal is to develop fast methods to predict and validate the region that is heated with mild ultrasound hyperthermia, developing methods that will be used in clinical treatment planning. In this treatment methodology, temperature sensitive drug delivery particles are injected and allowed to accumulate within a region of interest, typically over 6-24 hours. Ultrasound is then scanned through the volume of interest to locally increase the temperature by 2-40C for a short period, releasing a drug and greatly increasing its local concentration. In order to accomplish this goal, the following components have been developed in preliminary work: activatable drug delivery vehicles with enhanced stability, advanced ultrasound transducers integrated within a clinical ultrasound system, positron emission tomography (PET) and optical imaging probes to monitor the vehicle shell and core, methods to track particles and the encapsulated drug, a pharmacokinetic model using imaging data as the inputs, and lipoPEGpeptides targeted to tumor cells and tumor vasculature. Applying our new infrastructure, we have demonstrated that we can: target a significant fraction of drug-carrying particles to tumors (~up to 23% of the injected dose per gram following systemic administration), obtain a high (up to 33 dB) target to background ratio image of the vehicles, release model drugs within the region of interest while imaging the release optically, and enhance drug efficacy with ultrasound. In order to translate this technology into the clinic, algorithms and software for treatment planning and validation must be generated. Here, our specific aims are: first, develop fast methods to calculate the effective field and temperature distribution for varied beam geometries and scanning protocols;second, validate the field and temperature profiles in phantom;third, demonstrate rapid and effective drug release in implanted tumor models. Radiation force estimates of displacement and thermal strain are used to estimate the beam location. PUBLIC HEALTH RELEVANCE: Currently, one in 4 deaths in the United States is due to cancer. Available options for preemption and treatment are limited by the toxicity profiles of various drugs. As a result, substantial efforts have been directed to develop nanotechnology-based methods for increasing the efficacy and decreasing the toxicity of drug therapies. Ultrasound can be used to release a drug from a nanoparticle remotely and selectively, even within deep within tissues. In order to translate ultrasonic drug delivery into the clinic, here we develop methods to predict and validate ultrasound intensity and temperature profiles over an entire volume.